The design of an optimized chemical manufacturing process is very often a process as well, keeping in mind the goals of synthetic efficiency, waste reduction and use of materials having a reduced health risk. A manufacturing synthesis having a reduced environmental impact may employ a safer synthetic design by using minimally hazardous reagents and solvents, thus providing a new, more efficient and cost-effective process with positive environmental and economic impacts. The process of the present invention, while providing a pharmaceutically useful series of compounds, eliminates the use of known mutagenic reagents and chlorinated solvents. Accordingly, the synthesis of the present invention may reduce overall economic and environmental impact by using a reduced amount of reagents and solvents as well as less hazardous reagents and solvents, thereby reducing attendant disposal costs and the total cost of goods.
The synthesis of quaternary ammonium or phosphonium salt forms for a series of 3,4-dihydro-naphthalene, 2H-chromene, 8,9-dihydro-7H-benzocycloheptene and 2,3-dihydro-benzo[b]oxepine carbamoyl compounds as MCP-1 antagonists have been described (see Shiraishi M, Aramaki Y, Seto M, Imoto H, Nishikawa Y, Kanzaki N, Okamoto M, Sawada H, Nishimura O, Baba M and Fujino M, Discovery of Novel, Potent, and Selective Small-Molecule CCR5 Antagonists as Anti-HIV Agents: Synthesis and Biological Evaluation of Anilide Derivatives with a Quaternary Ammonium Moiety, J. Med. Chem., 2000, 43, 2049-2063; see also, U.S. Pat. No. 6,268,354 describing a pharmaceutical composition for antagonizing CCR5 comprising a quaternary ammonium salt form of an anilide derivative).
The synthesis of a salt form for N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]tetrahydro-2H-pyran-4-aminium chloride (TAK-779) has been described (see Ikemoto T, Ito T, Hashimoto H, Kawarasaki T, Nishiguchi A, Mitsudera H, Wackimasu M and Tomimatsu K, Development of a New Synthetic Route of a Non-Peptide CCR5 Antagonist, TAK-779, for Large Scale Preparation, Organic Process Research and Development, 2000, 4, 520-525; and, Ikemoto T, Nishiguchi A, Mitsudera H, Wakimasu M and Tomimatsu K, Convenient, Efficient Synthesis of TAK-779, a Non-Peptide CCR5 Antagonist: Development of Preparation of Various Ammonium Salts using Trialkylphosphite and N-Halogenosuccinimide, Tetrahedron, 2001, 57, 1525-1529)
The synthesis of 7-{4-[2-(butoxy)-ethoxy-phenyl}-N-(4-{methyl-(tetrahydro-2H-pyran-4-yl)amino}methyl]phenyl)-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide via an acid chloride intermediate has been described (see Ikemoto T, Ito T, Nishiguchi A, Miura S and Tomimatsu K, Practical Synthesis of an Orally Active CCR5 Antagonist, 7-{4-[2-(butoxy)-ethoxy-phenyl}-N-(4-{methyl-(tetrahydro-2H-pyran-4-yl)amino}methyl]phenyl)-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide, Organic Process Research and Development, 2005, 9, 168-173).
United States Patent Publication 2006/0293379, incorporated herein by reference in its entirety and for all purposes, describes substituted quaternary iodide salt compounds of Formula (I) that may be prepared using the process of the present invention. Additionally, all other documents cited herein are incorporated by reference in their entirety and for all purposes.